Nitric oxide (NO) is an important inter- and intracellular messenger implicated in the pathogenesis of septic shock. Inhibition of nitric oxide synthase (NOS) is under investigation as a treatment for hypotension in septic shock. In addition to the vasodilating effect of NO, this messenger also has affects on platelets and immune cells. In this investigation, we are examining the role of the NO pathway as a modulator of immune cell function. We have been unable to create conditions under which human phagocytes, in particular neutrophils, endogenously produce NO (VanDerVort, A. et.al., J Immunology, 1994. v.152:4102A109). Therefore, the ability of NO produced by other cells, such as endothelium and epithelium, to alter the function of human phagocytes is being explored. We have found that in addition to up-regulating tumor necrosis factor a production in human neutrophil preparations (J Immunol, 1994), NO modulates interleukin-8 message transcription and release in these cells. However, contrary to other reports, NO does not directly alter neutrophil chemotaxis. Recently, we have confirmed that NO regulates cytokine production using a U937 monocytic cell line transfected to express murine-inducible NOS. Further investigation of this effect has resulted in the description of a cyclic guanosine monophosphate-independent signaling pathway for NO. Future experiments are planned to better characterize this signal transduction pathway in both U937 cells and freshly isolated human phagocytes and document its effect on cell function (adhesion, cell- cell interactions, and differentiation).